Personne :
Guénard, Frédéric

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Université Laval. Institut sur la nutrition et les aliments fonctionnels
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Voici les éléments 1 - 9 sur 9
  • Publication
    Differential methylation in visceral adipose tissue of obese men discordant for metabolic disturbances
    (American Physiological Society, 2014-03-15) Guénard, Frédéric; Biron, Simon; Biertho, Laurent; Pérusse, Louis; Lescelleur, Odette; Vohl, Marie-Claude; Deshaies, Yves; Marceau, Simon; Tchernof, André
    Obesity is associated with an increased risk of Type 2 diabetes and cardiovascular diseases (CVD). The severely obese population is heterogeneous regarding CVD risk profile. Our objective was to identify metabolic pathways potentially associated with development of metabolic syndrome (MetS) through an analysis of overrepresented pathways from differentially methylated genes between severely obese men with (MetS+) and without (MetS-) the MetS. Genome-wide quantitative DNA methylation analysis in VAT of severely obese men was carried out using the Infinium HumanMethylation450 BeadChip. Differences in methylation levels between MetS+ (n = 7) and MetS- (n = 7) groups were tested. Overrepresented pathways from the list of differentially methylated genes were identified and visualized with the Ingenuity Pathway Analysis system. Differential methylation analysis between MetS+ and MetS- groups identified 8,578 methylation probes (3,258 annotated genes) with significant differences in methylation levels (false discovery rate-corrected DiffScore ≥ |13| ∼ P ≤ 0.05). Pathway analysis from differentially methylated genes identified 41 overrepresented (P ≤ 0.05) pathways. The most overrepresented pathways were related to structural components of the cell membrane, inflammation and immunity and cell cycle regulation. This study provides potential targets associated with adipose tissue dysfunction and development of the MetS.
  • Publication
    Accès libre
    Body mass index is associated with epigenetic age acceleration in the visceral adipose tissue of subjects with severe obesity
    (Springer, 2019-12-02) Guénard, Frédéric; Toro Martin, Juan de; Hould, Frédéric-Simon; Vohl, Marie-Claude; Lebel, Stéfane; Tchernof, André; Julien, François; Marceau, Simon
    Background There is solid evidence that obesity induces the acceleration of liver epigenetic aging. However, unlike easily accessible blood or subcutaneous adipose tissue, little is known about the impact of obesity on epigenetic aging of metabolically active visceral adipose tissue (VAT). Herein, we aimed to test whether obesity accelerates VAT epigenetic aging in subjects with severe obesity. Results A significant and positive correlation between chronological age and epigenetic age, estimated with a reduced version of the Horvath’s epigenetic clock, was found in both blood (r = 0.78, p = 9.4 × 10−12) and VAT (r = 0.80, p = 1.1 × 10−12). Epigenetic age acceleration, defined as the residual resulting from regressing epigenetic age on chronological age, was significantly correlated with body mass index (BMI) in VAT (r = 0.29, p = 0.037). Multivariate linear regression analysis showed that, after adjusting for chronological age, sex and metabolic syndrome status, BMI remained significantly associated with epigenetic age acceleration in VAT (beta = 0.15, p = 0.035), equivalent to 2.3 years for each 10 BMI units. Binomial logistic regression showed that BMI-adjusted epigenetic age acceleration in VAT was significantly associated with a higher loss of excess body weight following biliopancreatic diversion with duodenal switch surgery (odds ratio = 1.21; 95% CI = 1.04–1.48; p = 0.03). Conclusions Epigenetic age acceleration increases with BMI in VAT, but not in blood, as previously reported in liver. These results suggest that obesity is associated with epigenetic age acceleration of metabolically active tissues. Further studies that deepen the physiological relevance of VAT epigenetic aging will help to better understand the onset of metabolic syndrome and weight loss dynamics following bariatric surgery.
  • Publication
    Accès libre
    Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants
    (Nature Publishing Group, 2015-02-28) Allum, Fiona; Guénard, Frédéric; Shao, Xiaojian; Vohl, Marie-Claude; Lessard, Julie.; Simon, Marie-Michelle; Tchernof, André; Busche, Stephan; Caron, Maxime; Lambourn, John; Tandre, Karolina; Hedman, Asa K.; Kwan, Tony; Ge, Bing; Rönnblom, Lars; McCarthy, Mark I.; Deloukas, Panos; Richmond, Todd; Burgess, Daniel; Spector, T. D. (Timothy David); Marceau, Simon; Lathrop, Mark; Pastinen, Tomi; Grundberg, Elin
    Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targetedarrays or enrichment methodologies preferentially covering CpG-dense regions, tocharacterize sufficiently large samples. To overcome this limitation, we present here a newcustomizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), forsequencing functional methylomes, while simultaneously providing genetic variationinformation. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adiposetissue (AT) samples and public databases to design AT-specific panels. We establish itsefficiency for high-density interrogation of methylome variability by systematic comparisonswith other approaches and demonstrate its applicability by identifying novel methylationvariation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol,including atCD36. Our more comprehensive AT panel assesses tissue methylation andgenotypes in parallel atB4 andB3 M sites, respectively. Our study demonstrates thatMCC-Seq provides comparable accuracy to alternative approaches but enables more efficientcataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.
  • Publication
    Accès libre
    Common sequence variants in CD163 gene are associated with plasma triglyceride and total cholesterol levels in severely obese individuals
    (Longdom Publishing SL, 2014-11-27) Guénard, Frédéric; Marianne, Cormier; Biron, Simon; Deshaies, Yves; Biertho, Laurent; Pérusse, Louis; Lescelleur, Odette; Vohl, Marie-Claude; Marceau, Simon
    Objective: The CD163 glycoprotein is a member of the scavenger receptor cysteine-rich superfamily acting as an inflammatory modulator inducing anti-inflammatory pathways. Previous findings from our group identified this gene as being differentially expressed in visceral adipose tissue (VAT) of severely obese men with vs. without the metabolic syndrome. The current study aimed to test the association between CD163 gene polymorphisms and obesity-related metabolic complications. Methods: Sequencing of the CD163 gene region was conducted in 25 severely obese individuals. Eleven tagging SNPs (tSNP) were selected and tested for association with obesity-related complications in nearly 1900 severely obese individuals. To further explore potential mechanisms underlying associations identified, the impact of tSNPs on methylation levels of 3 CpG sites (two promoter and one intronic) and gene expression levels were tested in a subset of 14 individuals. Results: Rare allele carriers for rs7980201 demonstrated lower fasting total cholesterol (total-C) levels (p=0.01) while rs4883263 rare allele carriers had increased total-C (p=0.04) and triglyceride (TG) levels (p=0.01). An association identified between rs7980201 SNP and methylation level of a promoter CpG site (p=0.04) suggested an impact on CD163 gene methylation in VAT, but such association was not reflected at gene expression level. Conclusion: The current study reports association of CD136 gene variations with fasting total-C and TG levels and suggests that CD163 SNPs could contribute to the inter-individual variability observed in obesity-related metabolic complications.
  • Publication
    Accès libre
    Remodeling adipose tissue through in silico modulation of fat storage for the prevention of type 2 diabetes
    (BioMed Central, 2017-06-12) Chénard, Thierry; Guénard, Frédéric; Vohl, Marie-Claude; Tchernof, André; Carpentier, André; Najmanovich, Rafaël
    Background: Type 2 diabetes is one of the leading non-infectious diseases worldwide and closely relates to excess adipose tissue accumulation as seen in obesity. Specifically, hypertrophic expansion of adipose tissues is related to increased cardiometabolic risk leading to type 2 diabetes. Studying mechanisms underlying adipocyte hypertrophy could lead to the identification of potential targets for the treatment of these conditions. Results: We present iTC1390adip, a highly curated metabolic network of the human adipocyte presenting various improvements over the previously published iAdipocytes1809. iTC1390adip contains 1390 genes, 4519 reactions and 3664 metabolites. We validated the network obtaining 92.6% accuracy by comparing experimental gene essentiality in various cell lines to our predictions of biomass production. Using flux balance analysis under various test conditions, we predict the effect of gene deletion on both lipid droplet and biomass production, resulting in the identification of 27 genes that could reduce adipocyte hypertrophy. We also used expression data from visceral and subcutaneous adipose tissues to compare the effect of single gene deletions between adipocytes from each compartment. Conclusions: We generated a highly curated metabolic network of the human adipose tissue and used it to identify potential targets for adipose tissue metabolic dysfunction leading to the development of type 2 diabetes
  • Publication
    Accès libre
    The rare allele of DGKZ SNP rs10838599 is associated with variability in HDL-cholesterol levels among severely obese patients
    (Open Access Text Pvt. Ltd, 2016-05-12) Guénard, Frédéric; Pérusse, Louis; Hould, Frédéric-Simon; Deshaies, Yves; Marceau, Picard; Bégin, Stéphanie; Vohl, Marie-Claude; Lebel, Stéfane; Tchernof, André
    Introduction: Diacylglycerol kinase-zeta, one of the ten isoforms of DGKs expressed in mammals is an important enzyme of lipid metabolism. It catalyzes the interconversion of diacylglycerol and phosphatidic acid, two major second messengers. Its gene DGKZ has been previously identified as being overexpressed and undermethylated in visceral adipose tissue of patients with (MetS+) versus without (MetS-) the metabolic syndrome (MetS). Objective: The aim of this study was to investigate the associations between DGKZ gene polymorphisms (SNPs) and phenotypes related to MetS (BMI, waist girth, CRP, fasting glucose, lipid profile (triglycerides, total-cholesterol, LDL-cholesterol and HDL-cholesterol (HDL-C)), resting systolic and diastolic blood pressures). Methods: The study sample included 1752 severely obese participants who underwent bariatric surgery. Associations between the five selected tSNPs of DGKZ and features of the MetS were tested. The effects of these SNPs on DGKZ methylation and expression levels were tested in subgroups of 32 and 14 obese subjects, respectively. Correlations between methylation and expression levels were also computed. Results: Homozygotes for the rare allele of rs10838599 displayed higher plasma HDL-C concentrations compared to the other genotype groups (p=0.03). For gene methylation, only a trend with the cg05412031 CpG site (p=0.09) was found for the single significantly phenotype-associated SNP. There was no significant correlation between DGKZ methylation at cg05412031 and expression levels. Conclusion: These results suggest that DGKZ SNP rs10838599 modulates plasma HDL-C levels thereby its gene contributes to the inter-individual variability observed in the cardiometabolic risk profile of patients with severe obesity.
  • Publication
    Accès libre
    Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements.
    (Nature Publishing Group, 2019-03-14) Allum, Fiona; Guénard, Frédéric; Hedman, Åsa K.; Vohl, Marie-Claude; Shao, Xiaojian; Tchernof, André; Cheung, Warren A.; Vijay, Jinchu; Kwan, Tony; Simon, Marie-Michelle; Ge, Bing; Moura, Cristiano; Boulier, Elodie; Rönnblom, Lars; Bernatsky, Sasha; Lathrop, Mark; McCarthy, Mark I.; Deloukas, Panos; Pastinen, Tomi; Grundberg, Elin
    Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.
  • Publication
    Accès libre
    Genetic regulation of differentially methylated genes in visceral adipose tissue of severely obese men discordant for the metabolic syndrome
    (Elsevier, 2017-02-01) Guénard, Frédéric; Biron, Simon; Biertho, Laurent; Pérusse, Louis; Lescelleur, Odette; Vohl, Marie-Claude; Marceau, Simon (***WMS); Deshaies, Yves; Tchernof, André
    A genetic influence on methylation levels has been reported and methylation quantitative trait loci (meQTL) have been identified in various tissues. The contribution of genetic and epigenetic factors in the development of the metabolic syndrome (MetS) has also been noted. To pinpoint candidate genes for testing the association of SNPs with MetS and its components, we aimed to evaluate the contribution of genetic variations to differentially methylated CpG sites in severely obese men discordant for MetS. A genome-wide differential methylation analysis was conducted in visceral adipose tissue (VAT) of 31 severely obese men discordant for MetS (16 with and 15 without MetS) and identified ∼17,800 variable CpG sites. The genome-wide association study conducted to identify the SNPs (meQTL) associated with methylation levels at variable CpG sites revealed 2292 significant associations (P < 2.22 × 10−11) involving 2182 unique meQTLs regulating the methylation levels of 174 variable CpG sites. Two meQTLs disrupting CpG sites located within the collagen-encoding COL11A2 gene were tested for associations with MetS and its components in a cohort of 3021 obese individuals. Rare alleles of these meQTLs showed association with plasma fasting glucose levels. Further analysis conducted on these meQTL suggested a biological impact mediated through the disruption of transcription factor (TF)–binding sites based on the prediction of TF-binding affinities. The current study identified meQTL in the VAT of severely obese men and revealed associations of two COL11A2 meQTL with fasting glucose levels.
  • Publication
    A CpG-SNP located within the ARPC3 gene promoter is associated with hypertriglyceridemia in severely obese patients
    (S. Karger AG, 2016-04-08) Guénard, Frédéric; Biron, Simon; Toro Martin, Juan de; Deshaies, Yves; Biertho, Laurent; Pérusse, Louis; Lescelleur, Odette; Vohl, Marie-Claude; Tchernof, André; Marceau, Simon
    Aims: To test the potential association of cytosine-phosphate-guanine dinucleotides (CpG)-single-nucleotide polymorphisms (SNPs) located within actin-related protein 2/3 complex subunit 3 (ARPC3), a gene recently linked to adipogenesis and lipid accumulation, with metabolic syndrome (MetS) features in severely obese patients. Methods: Prioritized SNPs within the ARPC3 locus were genotyped and tested for associations with MetS features in a cohort of 1,749 obese patients with and without MetS. Association testing with CpG methylation levels was performed in a methylation sub-cohort of 16 obese men. Results: A significant association was found between the CpG-SNP rs3759384 (C>T) and plasma triglyceride (TG) levels (false discovery rate-corrected p = 3.5 × 10-2), with 0.6% of the phenotypic variance explained by the CpG-SNP, and with TT homozygotes showing the highest plasma TG levels (1.89 mmol/l). The carriers of the rs3759384 T allele also showed a significant decrease in methylation levels of the ARPC3 promoter-associated CpG site cg10738648 in both visceral adipose tissue and blood. ARPC3 expression levels showed a strong correlation with plasma TG levels (r = 0.70; p = 0.02). Conclusions: The increased plasma TG levels found in homozygous rs3759384 T allele carriers argue for a relevant role of this CpG-SNP in lipid management among obese individuals, which may be driven by an epigenetic-mediated mechanism.